RS-thioctic acid (DL-alpha-lipoic acid) is used in pharmaceutical formulations both in infusion solutions and also in solid galenic forms for oral administration. All references hereinbelow to thioctic acid relate both to the enantiomerically pure compounds (R- or S-thioctic acid) and also to the racemic mixture (R,S-thioctic acid) and mixtures with any proportions of enantiomers.
Synthetically obtained DL-thioctic acid which is used for this purpose is obtained via the first step of dihydrolipoic acid (6,8-dimercaptooctanic acid) by means of oxidation. The synthetic process may also be carried out by producing enantiomerically pure R- or S-thioctic acid from enantiomerically pure R- or S-dihydrolipoic acid and advantageously using this (D- or L-alpha-lipoic acid) DE 41 37 773.7, EP 0427247 (U.S. Application of Blaschke, Ser. No. 07/975,075, filed Nov. 12, 1992). Enantiomerically pure R-thioctic acid and S-thioctic acid is, however, also obtainable using the process described in German published patent 36 29 116 (U.S. Pat. No. 4,772,727).
The material hitherto available has not had a very favorable form for pharmaceutical processing; it was not free-flowing, leading to irregularities during filling and necessitating an increased use of auxiliary substances or an intensive granulation in order to produce pharmaceutical tablets. In addition, it tends to create dust which is a disadvantage from the point of view of safety provisions.
Processes are known from the literature for the preparation of pure, pharmaceutically useful, thioctic acid in a form favorable for galenic processing (Chem. Ber. 1959, 1177) in which the dimercaptooctanic acid is distilled and again purified by distillation after oxidation to thioctic acid in order to be finally obtained at -70.degree. C. in crystalline form from ethyl acetate. Another method (J.Am.Chem.Soc. 77(1955), 416) uses the viscous oil obtained after oxidation of dimercaptooctanic acid by concentration of the organic solvents. This is extracted several times with Skellysolve B, a fluctuating proportion of a "polymeric" material remaining.
The combined extracts are inoculated and crystallized at room temperature or for a few hours in a refrigerator. The recrystallization from Skellysolve B finally yields an analytically pure material with a melting point of 61.degree. C.-62.degree. C.
Another specification (J.Am.Chem.Soc. 77(1955) 5148) recommends cyclohexane for the extraction and crystallization, enantiomerically pure (+)-alpha-lipoic acid also being obtained in analogous manner (J. Chem. Soc. Perkin Trans. 1(1990), 1615). Crystallizates obtained in this manner display the X-ray diffractograms published by Reed et al., J.Am.Chem.Soc., 7(1953)1267 for (+)-alpha-lipoic acid and those published by Eli Lilly for DL-alpha-lipoic acid. [Transmission-X-ray diffractometer photos with Cu K.sub..alpha.1 -radiation (2 theta)].